One means of studying the in vitro release rate of drug substances from pharmaceutical formulations into simulated biological fluids is by dissolution testing. This type of testing is of particular importance in the study of sustained release formulations where drug release rates must be carefully controlled. Existing means for automating this type of testing includes the use of apparatus designed to sample from the dissolution vessels continuously or discretely.
In the continuous sampling from dissolution vessels, a single probe per dissolution vessel is employed. An in-line filter assures the absence of particulates being sampled. Since the sample is drawn in a more or less continuous fashion, clogging of the filter comprises a drawback in this type of operation.
Discrete sampling is normally accomplished using apparatus which incorporates a disposable tip filter removably affixed to the end of the sampling probe. The filter element is changed before sample is retrieved from another dissolution vessel in order to guard against the carrying over of any sample. Thus, filter clogging is not a concern in the discrete type of sampling as in the continuous type aforediscussed. A limitation of the discrete sampling method however is the need to change tip filters before sample retrieval from different dissolution vessels.
Automated dissolution sampling apparatus are commercially available from Zymark Corporation of Hopkinton, Mass., for example, and Van-Kel Industries of Edison, N.J., among others. The commercial automatic samplers often include arms or extensions performing sampling operations in a sequence governed by microprocessor controlled robotics, as in the present invention. Existing automated sampling apparatus however does not permit a single in-line filter and a single probe to sample from a plurality of dissolution vessels.
The present invention provides a discrete robotic sampling apparatus which employs a single in-line filter for ease of operation, while requiring but a single probe for sampling from a plurality of dissolution vessels. The single in-line filter and single probe of the present apparatus have been successfully and repeatedly used for retrieving samples from as many as 24 dissolution vessels over a time period extending beyond 24 hours.
The apparatus employs a reversible pump programmed to pull several milliliters of sample from a dissolution vessel through the hypodermic needle and in-line filter of the probe. The pump is then reversed to force filtered sample through the filter in the reverse direction to clear it of particulate matter retained by the filter. Backflushing of the filter eliminates clogging thereof and the possibility of transferring particulates to the sample container. By backflushing with the filtered sample rather than with external fluid, the need for additional valves and means for controlling the valves is eliminated as well as permitting faster sampling rates.
The apparatus is also provided with a clean-out mode between sample retrievals from different dissolution vessels to insure an absence of residual portions of an older sample from mixing with or being carried over to successive samples.